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Copyright 2015 American Medical Association. All rig hts reserved.

Treatment andOutcome

of Thrombolysis-RelatedHemorrhage

A Multicenter Retrospective Study

Shadi Yaghi, MD;Amelia K. Boehme, MSPH,PhD;JamilDibu,MD; Christopher R. LeonGuerrero, MD;

Syed Ali, MD;Sheryl Martin-Schild,MD, PhD; Kara A. Sands,MD; AliRezaNoorian,MD;

ChristinaA. Blum, MD;Shuchi Chaudhary, MD;LeeH. Schwamm,MD; David S.Liebeskind,MD;

Randolph S.Marshall, MD, MS;Joshua Z. Willey, MD, MS

IMPORTANCE Treatments for symptomatic intracerebral hemorrhage (sICH) are based on

expert opinion, with limited data available on efficacy.

OBJECTIVE To better understand the natural history of thrombolysis-related sICH, with a

focuson theefficacy of various treatments used.

DESIGN, SETTING, AND PARTICIPANTS Multicenterretrospective study between January 1,

2009, andApril 30, 2014, at 10 primary and comprehensive stroke centers acrossthe UnitedStates. Participantswere allpatients with sICH, using thedefinition by the Safe

Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST), whichincluded a

parenchymal hematomatype 2 and at least a 4-point increase in theNationalInstitutesof

Health Stroke Scale score.

MAINOUTCOMES AND MEASURES The primary outcome was in-hospital mortality, and the

secondary outcome washematoma expansion, definedas a 33%increasein thehematoma

volume on follow-up imaging.

RESULTS Of 3894 patients treated with intravenous recombinant tissue plasminogen

activator (rtPA) within4 hours after symptom onset of ischemic stroke, 128(3.3%) had

sICH. The mediantime from initiation of rtPA therapy to sICH diagnosis was470 minutes

(range, 30-2572 minutes),and themedian time from diagnosisto treatmentof sICH was

112minutes (range, 12-628 minutes).The in-hospital mortalityrate was 52.3% (67 of 128),

and 26.8% (22 of 82)had hematoma expansion. In themultivariablemodels, code status

changeto comfort measures after sICH diagnosiswas the sole factor associated with

increased in-hospital mortality (odds ratio, 3.6; 95% CI, 1.2-10.6). Severe hypofibrinogenemia

(fibrinogen level,

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Intravenous thrombolytic therapy with recombinant tis-

sue plasminogen activator (rtPA) improves the outcome

of patients with ischemic stroke treated within hours

after symptom onset. The most serious complication is

symptomatic intracerebral hemorrhage (sICH), which was

reported in % of patients with acute ischemic stroke in the

National Institute of Neurological Disorders and Stroke rtPA

trials. Despite its infrequent occurrence, sICH is associated

with significant morbidity and a high mortality rate

approaching %. Recommendations by the American

Heart Association and the American Stroke Association for

the management of sICH are to replace coagulation factors

with cryoprecipitate and to transfuse with platelets. While

prior studies- have investigated clinical and imaging risk

factors for sICH, to our knowledge, the efficacyof these treat-

ment recommendations has been examined in few investiga-

tions, which have been largely single-center studies. Prior

evidence has shown substantial variability in treatment prac-

tices and limited success in halting sICH. These studies are

limited by small sample sizes and incomplete accounting for

confounders, such as code status change after sICH diagno-

sis. Therefore, we pooled contemporary data on treatment

practices across several high-volume stroke centers in the

United States with the objective to study the natural history

of thrombolysis-related sICH, with a particular focus on the

potential efficacy of various treatments. We also sought to

identify key variables in the acute stroke treatment period

that contributed to a high in-hospital mortality rate.

Methods

StudyPopulation

This was a multicenter retrospective study of sICH after intra-

venous rtPA treatment at US primary and comprehensive

stroke centers (Columbia University Medical Center, Cleve-

land Clinic Foundation, Washington University in St Louis,

University of Arkansas for Medical Sciences, Tulane Univer-

sity, The University of Alabama at Birmingham, UCLA [Uni-

versity of California, Los Angeles], Hospital of the University

of Pennsylvania, University of Oklahoma, and Massachusetts

General Hospital) (Figure ). Patients with sICH based on the

National Institute of Neurological Disorders and Stroke defi-

nition were identified via local Get With the Guidelines

stroke databases at each center. We identified patients using

the comprehensive National Institute of Neurological Disor-

ders and Stroke definition and only included patients who

met the criteria for the Safe Implementation of Thrombolysis

in Stroke-Monitoring Study (SITS-MOST) definition. Confir-

matory and additional data were obtained directly from hos-

pital patient records, including hematoma characteristics, the

time to detection and treatment, and in-hospital mortality.

We reviewed the medical records of all patients identified

and included only patients with sICH, using the definition by

the SITS-MOST. This definition includes the presence of a

parenchymal hematoma accounting for more than one-third

of the infarct volume (parenchymal hematoma type ) on

head computed tomography (CT) and at least a -point

increase from the baseline National Institutes of Health

Stroke Scale (NIHSS) score. In prior investigations, the pres-

ence of a parenchymal hematoma type has correlated well

with mortality and poor outcome. The primary outcome

herein was in-hospital mortality, and posthospitalization out-

comes were not available at most centers. The secondary out-

come was hematoma expansion, defined as a %increase in

the hematoma volume on follow-up imaging. The primary

predictor of interest was the receipt of any type of treatment

for sICH.

Additional variables were examined as predictors of

in-hospital mortality and hematoma expansion. First were

Figure 1. PatientFlowchart

3 Centers did not participate

46 Patients with no follow-up imaging

Hematoma expansion cohort In-hospital mortality cohort

13Academic centers invited

82 Patients with follow-up imaging 37Patients with withdrawalof care after diagnosis

91 Patients without withdrawalof care after diagnosis

10 Centers contributed

3894 Patients who received intravenousrtPA, among whom 128 had sICHusing SITS-MOST definition

128Patients with sICH

rtPAindicatesrecombinant tissueplasminogen activator; sICH,symptomatic intracerebral hemorrhage; and SITS-MOST, SafeImplementationof Thrombolysis in

Stroke-Monitoring Study.

Research Original Investigation Treatment and Outcome of Thrombolysis-Related Hemorrhage

1452 JAMANeurology December 2015 Volume72, Number12 (Reprinted) jamaneurology.com


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pretreatment factors, including demographics (age, race/

ethnicity, and sex), stroke risk factors (hypertension, diabetes

mellitus, hyperlipidemia, congestive heart failure, history of

cancer, and renal disease), antiplatelet or anticoagulant use

before thrombolysis, admission NIHSS score, and code status

change to comfort care measures after sICH diagnosis. Sec-

ond were laboratory measures, including pretreatment blood

glucose level, coagulation laboratory values after sICH diag-

nosis (plasma thromboplastin time and international normal-

ized ratio), and fibrinogen level after sICH diagnosis (

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than those receiving the diagnosis after hours (median

score, vs ; P= .). The sICH diagnosis was made more

than hours after initiation of intravenous rtPA therapy in

.% ( of ) of patients.

In-Hospital Mortality

There was a nonsignificant suggestion of lower in-hospital

mortality in patients receiving any treatment for sICH vs no

treatment (.% [ of ] vs .% [ of ], P= .). The

receipt of an endovascular neurointerventional procedure

(.% [ of ] vs .% [ of ], P= .), a higher median

hematoma volume ( vs mL, P= .), and code status

change to comfort measures in the first hours (.% [

of ] vs .% [ of ], P< .) were the only statistically

significant factors associated with a higher in-hospital mor-

tality rate in the univariable analysis. The association

between lower in-hospital mortality and surgical treatment

vs nonsurgical treatment was nonsignificant (.% [ of ]vs .% [ of ], P= .). Other variables did not differ

between the groups of those who died and those who sur-

vived and are summarized in Table . In the multivariable

logistic regression analyses, the only variable associated with

increased in-hospital mortality was code status change to

comfort measures in the first hours after sICH diagnosis

(odds ratio, .; % CI, .-.). A sensitivity analysis was

performed that excluded patients with code status change

to comfort measures in the first hours, and the results

remained unchanged.

Table2. Univariable Analysisof Clinical,Radiological,and LaboratoryPredictors of In-Hospital Mortalityand HematomaExpansion

Variable

In-Hospital Mortality Cohort Hematoma Expansion Cohort

No Mortality(n = 61)

Mortality(n = 67) PValue

No HematomaExpansion(n = 60)

Hematoma Expansion(n = 22) PValue

Age, median (range), y 74 (23-99) 75 (42-94) .87 75 (23-94) 66 (36-85) .05

Male sex, No. (%) 27 (44.3) 36 (53.7) .28 30 (50.0) 7 (31.8) .07

Black race/ethnicity, No. (%) 17 (27.9) 21 (31.3) .51 18 (30.0) 6 (27.2) .98

Hypertension, No. (%) 47 (77.0) 59 (88.1) .11 46 (76.7) 19 (86.4) .54

Diabetes mellitus, No. (%) 15 (24.6) 23 (34.3) .25 15 (25.0) 7 (31.8) .58

Hyperlipidemia, No. (%) 30 (49.1) 38 (56.7) .48 33 (55.0) 11 (50.0) .80

Prior stroke, No. (%) 16 (26.2) 23 (34.3) .34 16 (26.7) 7 (31.8) .78

Warfarin sodium use, No. (%) 1 (1.6) 4 (5.9) .18 1 (1.7) 2 (9.1) .16

ASPECTS score, median (range) 10 (6-10) 10 (5-10) .67 10 (5-10) 10 (5-10) .57

Neurointerventional procedure,No. (%)

4 (6.6) 14 (20.9) .01 8 (13.3) 4 (18.2) .23

Type of treatment, No. (%)

Vitamin K 3 (4.9) 4 (5.9) .29 3 (5.0) 2 (9.1) .29

Cryoprecipitate 22 (36.1) 18 (26.9) .26 17 (28.3) 10 (45.4) .07

Aminocaproic acid 2 (3.3) 0 .23 2 (3.3) 0 .53

Fresh frozen plasma 11 (18.0) 15 (22.4) .54 11 (18.3) 6 (27.3) .16

Prothrombin complexconcentrate

1 (1.6) 2 (2.9) .40 3 (5.0) 0 .39

Recombinant factor VIIa 1 (1.6) 2 (2.9) .40 2 (3.3) 1 (4.6) .44

Platelet transfusion 20 (32.8) 17 (25.4) .36 13 (21.7) 11 (50.0) .01

Surgical decompressivecraniotomy or hematomaevacuation

11 (18.6) 7 (10.9) .10 6 (10.0) 4 (18.2) .17

Any treatment 29 (47.5) 20 (29.9) .11 30 (50.0) 13 (59.1) .47

Code status change to comfortmeasures in the first 24 h, No. (%)

7 (11.5) 30 (44.8)

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HematomaExpansion

Follow-up CT was performed in of patients (.%).

The baseline characteristics were similar between patients

with and without follow-up CT (eTable in theSupplement).

Hematoma expansion was observed in of patients

(.%). In the univariable analysis, the receipt of any medi-

cal treatment vs no treatment was not associated with hema-

toma expansion (.% [ of ] vs .% [ of ],

P= .). Patients with hematoma expansion were more likely

to receive platelet transfusion (.% [ of ] vs .% [

of ], P= .) and have severe hypofibrinogenemia (fibrino-gen level,

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In our study, we found that diverse treatments were used,

which may have contributed to our neutral results. Hemo-

static agents used at the various centers included vitamin K,

freshfrozen plasma, cryoprecipitate, prothrombincomplex con-

centrate,aminocaproicacid, and recombinantfactor VIIa.Sur-

gery(decompressivecraniotomyor hematomaevacuation)was

the only treatment associated with reduced in-hospital mor-

tality in our sICH cohort, although the associationwas nonsig-

nificant. This finding was previously noted in an acute myo-

cardial infarction study, in whichamongpatientstreated with

thrombolytictherapytheoutcome of patientswith thromboly-

sis-related intracerebral hemorrhage improved after surgical

treatment as opposed to nonsurgical treatment.Surgical inter-

vention may bebeneficialin a small proportion of patients with

spontaneous intracerebral hemorrhage,andparallelscouldbe

drawn to sICH. However,the benefit of surgerymay simply be

a reductionin mortality, leavingsurvivors withsubstantial mor-

bidity and disability.

Our study has several limitations, includingits retrospec-

tivenatureand wide variationsin the management and treat-

mentprotocols usedby participatingcenters. Also, because few

patientsreceivedeach of thesICHtreatments,it is possible that

the effects of therapy may be underestimated. However, this

trial is the first multicenter study, to our knowledge, that ex-

amines real-world treatments used by comprehensive stroke

centers and includes codestatus change to comfort measures

in theanalysis. While ouranalysis includedseveral confound-

ersof outcome(eg,admissionNIHSS score,Alberta StrokePro-

gramEarly CT Score[ASPECTS] score, and codestatuschange

to comfort measures after sICH diagnosis), we lacked data on

other potential confounders, such as adequate blood pres-

sure control and certain neuroimaging findings.

Conclusions

Thereis significantroom forimprovement in reducing thetime

from initiation of rtPA therapy to sICH diagnosisand thetime

to treatment of sICH. Despite the potential thrombotic com-

plications of more aggressive treatments, agents for reversal

of coagulopathy with a high efficacy and short onset of ac-

tionshouldbe studied to helpimprove themortality andmor-

bidity of sICH. No current treatments factor in the contribu-

tion ofa breakdown ofthe blood-brainbarrier inacuteischemic

stroke, an important gap in treatment considerations. Col-

laborativeeffortsacross disciplinesand institutions areneeded

to identify the reversal agents that can lead to improved out-

come in patients with postthrombolysis hemorrhage. Larger

multicenter prospective studies may help generate an algo-

rithm toscreenanddiagnose high-risk patients earlier andmore

aggressively reverse the coagulopathy induced by rtPA when

sICH occurs.

ARTICLE INFORMATION

Accepted for Publication: July28, 2015.

Published Online: October 26,2015.

doi:10.1001/jamaneurol.2015.2371.

Author Affiliations: Departmentof Neurology,

Columbia UniversityMedical Center,New York,

New York (Yaghi,Boehme, Marshall, Willey);

currently withthe Departmentof Neurology,BrownUniversity, Providence,Rhode Island(Yaghi);

Departmentof Neurology, ClevelandClinic

Foundation,Cleveland, Ohio (Dibu); Departmentof

Neurology, WashingtonUniversity in St Louis,

St Louis,Missouri (Leon Guerrero); Departmentof

Neurology, Universityof Arkansas for Medical

Sciences,Fayetteville (Ali);Department of

Neurology, Tulane University, New Orleans,

Louisiana (Martin-Schild); Departmentof

Neurology, TheUniversityof Alabamaat

Birmingham,Birmingham(Sands);Department of

Neurology, UCLA (Universityof California,

LosAngeles), forthe UCLA Acute Stroke

Investigators, Los Angeles (Noorian, Liebeskind);

Departmentof Neurology, Hospital of the

Universityof Pennsylvania, Philadelphia (Blum);

Departmentof Neurology, Universityof Oklahoma,Norman(Chaudhary); Departmentof Neurology,

Massachusetts General Hospital, Boston

(Schwamm).

Author Contributions: Dr Yaghi andMs Boehme

had fullaccessto all the datain the study and take

responsibility forthe integrityof thedataand the

accuracy of thedataanalysis.

Acquisition, analysis, or interpretation of data:

Boehme, Dibu,Leon Guerrero, Ali, Martin-Schild,

Sands, Noorian, Blum,Chaudhary.

Drafting of themanuscript:Yaghi.

Critical revision of themanuscriptfor important

intellectual content: Dibu,Leon Guerrero, Ali,

Martin-Schild,Sands, Noorian, Blum,Chaudhary,

Schwamm, Liebeskind, Marshall, Willey.

Administrative, technical, or material support: Yaghi.

Conflict of Interest Disclosures: Dr Yaghi reported

receiving funding from the Stroke Trials Network

(StrokeNet)of theNational Instituteof Neurological

Disorders and Stroke. Dr Liebeskindreported being

a consultantfor Stryker andCovidien. DrWilleyreported beinga consultantfor HeartWare Inc.

No otherdisclosureswere reported.

Additional Contributions: SalahG. Keyrouz,MD

(Washington Universityin St Louis), Archana

Hinduja, MD (Universityof Arkansas for Medical

Sciences),Nicolas Bianchi, MD (Universityof

Arkansas for Medical Sciences),Brett Cucchiara, MD

(Hospital of the Universityof Pennsylvania),and

Joao Gomes,MD (ClevelandClinic Foundation)(all

inthe Departmentof Neurology at their respective

institutions) collaborated in the study.

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Treatment and Outcome of Thrombolysis-RelatedHemorrhage Original Investigation Research

jamaneurology.com (Reprinted) JAMA Neurology December 2015 Volume72,Number 12 1457

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